1. Field of the Invention
The present invention relates to impaired wound healing, and particularly to a method of treating diabetes-related impaired wound healing.
2. Description of the Related Art
Proper cutaneous wound healing involves a progression of hemostasis/clotting, inflammation, cell proliferation and migration, and new tissue remodeling. This process depends on a multitude of inter- and intracellular signaling cascades. Typically the final steps of wound healing include closure several days to two weeks after injury, which is followed by remodeling of the new tissue. This process can be disrupted by stresses on the body, including patient habits, such as smoking and alcohol consumption, or by physical conditions, such as aging, stress, obesity and diabetes. Each of these factors impacts the normal processes involved in cutaneous cellular processes and signaling that are important to wound healing, and can result in a wound that suffers delayed or impaired wound healing, or in the worst case, a wound which fails to close at all.
Impairment of wound healing is a serious medical condition with enormous ramifications, and can lead to serious infection and amputation, for example. Non-healing cutaneous wounds affect 3 to 6 million Americans per year, with 85% of sufferers over the age of 65. Estimates of medical costs range in the billions of dollars per year in the US.
The processes of cell proliferation and migration are particularly important in normal wound healing. These processes are regulated by a balance of pro-inflammatory and anti-inflammatory signaling molecules in the wound environment. Pro-inflammatory cytokines, such as TNF-α, while important for fighting infection, can act antagonistically with anti-inflammatory cytokine growth factors, such as TGF-β, which promote cell proliferation, migration and differentiation. TNF-α influences the phenotype of macrophage immune cells, which change their secreted molecules in response to the presence of TNF-α to reinforce the inflammatory state and inhibit the cell migration/proliferation state within the wound.
Estrogen has also been shown to modulate the rate of wound healing. For example, the cutaneous wounds of postmenopausal women tend to heal more slowly than those of younger women, and estrogen replacement therapy (ERT) tends to ameliorate the slower rate of healing. Estrogen counteracts the effects of TNF-α and encourages cell proliferation and differentiation, partially through promoting an anti-inflammatory phenotype in which immune cells secrete TGF-β. Anti-inflammatory macrophages can be identified by the cytokines they secrete, as well as the pattern of protein receptors they display on their surface. TREM2 is a detectable receptor that is expressed on the surface of macrophages that exhibit an anti-inflammatory phenotype, but has only been observed in visceral tissue, such as adipocytes and colon tissue. Macrophages require exposure to the cytokines IL-4 and IL-13 before expressing TREM2. However, these cytokines are not expressed in cutaneous tissue. Changes in expression of TREM2 have been observed in diabetes, but only in adipocytes, where an upregulation was observed that was deemed causative in the etiology of the disease.
Thus, a method of treating diabetes-related impaired wound healing solving the aforementioned problems is desired.